Molecular Mechanisms Regulating Exocytosis
My research is focused on the examining the molecular mechanisms that regulate exocytosis and have used the neuroendocrine islet beta cell as the major model, and to a lesser extent, also the epithelial pancreatic acinar cell.

My laboratory has made some pioneering observation demonstrating SNARE proteins, originally shown to be involved in the primitive yeast constitutive secretory machinery and the highly regulated neurotransmitter release, to be conserved in non-neuronal cells to regulate secretion.

The current emphasis and working hypothesis of this lab is directed towards the identification of the putative functional domains within these SNARE proteins which physically and functionally interact with islet beta cell membrane ion channels which regulate the intricate sequence of ion fluxes (K+, Ca2+), membrane potential and exocytotic fusion events leading to secretion.

Insights gained from such studies will eventually lead to the elucidation of how these distal components of the insulin exocytotic machinery could be dysregulated to explain the distorted insulin secretion in diabetes; and more importantly, to identify therapeutic targets revealed by these SNARE-ion channel interactions.

This lab has in place the full spectrum of functional assays for the islet beta cell, including islet perifusion assays, state-of-the-art patch clamp electrophysiology methods (including capacitance measurements, photorelease of caged compounds, and single channel recording), real-time high-resolution digital fluorescence imaging of single granule exocytosis by evanescent microscopy, protein interactions by FRET imaging analysis, and cytoplasmic ion fluxes. As well, this lab has in place complementary assays in biochemistry (immunoprecipitation), molecular biology (site-specific mutagenesis) and gene transfer of cell lines and islets (adenovirus and lentivirus).

This research program is supported by Canadian (Canadian Institute of Health Research, Canadian Diabetes Association, Canadian Association of Gastroenterology) and international (NIH, Juvenile Diabetes Research Foundation) funding agencies.

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